The death receptors of the TNFR family induce apoptosis via a conserved cytoplasmic domain, designated the death domain, which helps in the recruitment of the adaptor protein FADD and subsequent activation of the caspase cascade via the recruitment and cleavage of pro-caspase 8. XEDAR is a recently isolated member of the TNFR family that is highly expressed during embryonic development and controls ectodermal differentiation by binding to its ligand, EDA-A2. Although XEDAR does not contain a death domain, it nevertheless possesses the ability to induce apoptosis. Our hypothesis is that XEDAR induces apoptosis via a unique signal transduction pathway, since it neither possesses a death domain nor interact with the known death domain-containing adaptor proteins FADD or TRADD. The broad long-term objective of this proposal is to better understand the molecular mechanisms underlying this unique apoptosis-inducing activity of XEDAR. This goal will be achieved by checking the interactions of XEDAR with proteins known to be involved in apoptosis using an antibody array and identifying novel interacting partners using a Bacterial Two-hybrid system. We hope that the above studies will not only lead to a better understanding of the process of ectodermal differentiation but will also lead to novel strategies for the diagnosis and treatment of patients with ectodermal dysplasias and cancers showing XEDAR over expression.